Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Abstract

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (R01 NS055925 and R21 NS101312), Iowa Center for Advanced Neurotoxicology (ICAN), and Salsbury Endowment (Iowa State University, Ames, IA, USA) to RNS. The authors acknowledge and regret not being able to include several references due to lack of space.

Disclosures and Competing Interests

The ISS-N1 target (US Patent# US7838657) was discovered in the Singh laboratory at UMass Medical School (MA, USA). Inventors, including RN Singh, NN Singh and UMASS Medical School, are currently benefiting from licensing of the ISS-N1 target to Ionis Pharmaceuticals and Biogen. Iowa State University holds intellectual property rights on GC-rich and ISS-N2 targets. Therefore, inventors including RN Singh, NN Singh and Iowa State University could potentially benefit from any future commercial exploitation of GC-rich and ISS-N2 targets.